Abstract This project will develop a novel infrared-based neuro-stimulation tool for specifically modulating neural circuitry. Transcranial infrared brain stimulation (TIBS) at 1064 nm will be developed as a new tool for non- invasive neuromodulation of the human brain. TIBS with low-power density (mW/cm2) and high-energy density (J/cm2) monochromatic laser is safe and can potentially modulate human brain function in a non-thermal manner. The mechanism of TIBS is based on the premise that infrared laser gives rise to photo-oxidation of cytochrome c oxidase (CCO), the respiratory enzyme in mitochondria that catalyzes the metabolic use of oxygen. The brain is critically dependent on oxygen metabolism for its physiological functions. Recently, our team has shown that TIBS delivered to the human prefrontal cortex results in significant increases of cerebral metabolism and oxygenation. These new and promising results have encouraged us to respond to the RFA, for developing TIBS as a novel non-invasive neuromodulation tool. Compared to existing electrical and magnetic tools for neuromodulation, TIBS (1) has no need to worry about excitatory versus inhibitory setup, (2) is easy to select stimulation site given the desired cortical region for stimulation, (3) has no need to design complicated probe montage, (4) can control spatial focality by varying the laser exposure aperture, (5) produces minimal discomfort on the participant?s head without any risk of seizures, (6) is low-cost, portable, and easy to move along with the participants, (7) has solid scientific premise and understanding of its working mechanism supported by many animal studies and recent human investigations. (8) While TIBS may be more effective to cortical regions because it uses infrared light with the limitation of penetration depth, our preliminary data show that TIBS does modulate deeper regions of the human brain and alter brain circuitry across the entire brain. The proposed project has two highly-focused, specific aims that will involve non-invasive controlled studies of healthy participants in three sites of the University of Texas. Aim 1 will determine the penetration depth, thermal effects, spatial resolution, and mechanism of TIBS delivered on the human forehead. The hypothesis for Aim 1 is that TIBS can reach the human cortex non-invasively and can significantly increase the oxidized state of CCO and promote cerebral oxygenation. Aim 2 will map and image large-scale, dynamic, electrophysiological and hemodynamic effects in neural circuitry that interact in both time and space during and after prefrontal TIBS. The hypothesis for Aim 2 is that prefrontal TIBS modulates electrophysiological and hemodynamic functions in a fronto-parieto-occipital network. We will accomplish these aims by an expert multidisciplinary team that will utilize advanced multi-modal optical imaging and electrophysiological methods with high spatiotemporal resolution, including diffusion optical tomography based on near-infrared spectroscopy techniques and EEG brain tomography. The success of this project will develop TIBS as a new non-invasive neuromodulation tool for future research and treatment of diverse brain disorders.